Alcohol abuse is a major social and economic problem for which current drug treatments are inadequate. A primary difficulty with the development of novel treatments for alcoholism is that the molecular nature of the interaction of the nervous system with the drug is incompletely understood. Alcohol is a small, easily diffusible molecule that probably interacts with many proteins in all neurons. A significant challenge for researchers is to determine which interactions are important for altering nervous system function and, ultimately, for the development of addiction. The nervous system mounts a dynamic response to exposure to alcohol that consists of several levels of the development of tolerance. The development of tolerance is important in the etiology of addiction. Variation in the ability to develop tolerance is an important component of the genetic diversity that predicts an individualbs propensity to abuse alcohol. We study the molecular mechanics of acute tolerance to ethanol, which develops during a single ethanol exposure. In mammals, this is observed as a recovery of coordination and cognitive ability at a blood ethanol level that is higher than the level that intoxicated the animal initially. In Caenorhabditis elegans (C. elegans), we observe acute tolerance as a recovery of coordinated locomotion during a single exposure to a constant dose of ethanol. C. elegans is an excellent model for the study of neural function because its extremely simple and well-characterized nervous system (302 neurons) contains at least 118 different neuronal cell types and uses many of the same neurotransmitters as are used by the mammalian brain. C. elegans genetics provides a facile means of dissecting nervous system function, and can be used effectively to address questions of drug effects on neurons. This project is designed to determine the molecular mechanisms of the development of acute tolerance. We will take a forward genetics approach by genetically screening for mutations that disrupt the development of acute tolerance to ethanol. The specific aims of this proposal are: 1- Genetically screen for mutations that disrupt development of acute tolerance to ethanol. 2- Molecularly characterize several of the mutations isolated in the genetic screen. 3- Characterize the function of the genes identified in Specific Aim 2 in acute tolerance. Together, the specific aims of this proposal are designed to thoroughly examine the molecular mechanisms of development of AFT. PUBLIC HEALTH RELEVANCE The project aims to use a forward genetic screen to identify genes in the nematode C. elegans that are required for the development of acute tolerance to ethanol. If the discovered genes are related to human genes then variation in those genes or in genes that regulate their activity or expression is likely to impact on an individual's initial response to alcohol and therefore could predispose that individual to alcoholism.